Risk factors for hospital-acquired pneumonia in hip fracture patients: A systematic review and meta-analysis

Background: This study aimed to comprehensively assess the prevalence and risk factors for Hospital-acquired pneumonia (HAP) in hip fracture patients by meta-analysis. Methods: Systematically searched 4 English databases and 4 Chinese databases from inception until October 20, 2022. All studies involving risk factors of HAP in patients with hip fractures will be considered. Newcastle-Ottawa Scale was used to evaluate the quality of the included studies. The results were presented through Review Manager 5.4 with the pooled odds ratio (OR) and 95% confidence interval. Results: Of 35 articles included in this study, the incidence of HAP was 8.9%. 43 risk factors for HAP were initially included, 23 were eventually involved in the meta-analysis, and 21 risk factors were significant. Among them, the 4 most frequently mentioned risk factors were as follows: Advanced age (OR 1.07, 95% CI 1.05–1.10), chronic obstructive pulmonary disease (COPD) (OR 3.44, 95% CI 2.83–4.19), time from injury to operation (OR 1.09, 95% CI 1.07–1.12), time from injury to operation ≥ 48 hours (OR 3.59, 95% CI 2.88–4.48), and hypoalbuminemia < 3.5g/dL (OR 2.68, 95% CI 2.15–3.36). Discussion: Hip fracture patients diagnosed with COPD have a 3.44 times higher risk of HAP compared to the general hip fracture patients. The risk of HAP also increases with age, with patients over 70 having a 2.34-fold higher risk and those over 80 having a 2.98-fold higher risk. These findings highlight the need for tailored preventive measures and timely interventions in vulnerable patient populations. Additionally, hip fracture patients who wait more than 48 hours for surgery have a 3.59-fold higher incidence of HAP. This emphasizes the importance of swift surgical intervention to minimize HAP risk. However, there are limitations to consider in this study, such as heterogeneity in selected studies, inclusion of only factors identified through multivariate logistic regression, and the focus on non-randomized controlled trial studies.


Introduction
Hip fractures are a major public health concern, with approximately 4.5 million cases worldwide annually and an expected increase to 21 million by 2060. [1]Hip fractures are associated with a high mortality rate, reaching 8.4% to 36% within 1 year of the fracture over the age of 70. [2]8] Epidemiological evidence shows that the incidence of postoperative HAP after hip fracture typically ranges from 5% to 15%, and that HAP in hip fracture patients increases mortality by 27-43%, length of hospital stay by 56%, and the risk of WY and XS have contributed equally to this work.

The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
readmission by 8-fold. [6,9]Furthermore, there is limited research on strategies for preventing HAP.These strategies may include early mobilization after surgery, oral care, inhalation prophylaxis measures, and the use of prophylactic antibiotics.The implementation of clinical preventive strategies is hindered by the presence of ambiguous underlying risk factors.Therefore, identifying the risk factors for HAP in hip fracture patients and preventing its occurrence is essential for optimizing perioperative care, predicting postoperative outcomes, and reducing mortality. [10]revious studies and meta-analyses have explored potential risk factors for pneumonia in hip fracture patients after hospitalization.However, the limitations of these studies include small sample sizes and a lack of inclusion of Chinese literature (gender, age, anemia, duration of surgery, length of hospital stay, and some laboratory biomarkers [2,[11][12][13][14] ), which may restrict the generalizability of the research findings and increase the risk of selection bias and geographical bias.Moreover, many studies only analyzed risk factors for HAP after hip fracture, without further subgroup analysis of these risk factors.This heterogeneity in previous study design may mislead the conclusions.To address this issue and improve comparability, the present study conducted subgroup analyses for risk factors with high heterogeneity.Additionally, recent publications may provide new evidence for the previous results.
This meta-analysis aims to investigate and summarize the risk factors for HAP in hip fracture patients by including more literature and employing rigorous statistical methods.It will report all risk factors currently associated with HAP and further explore important risk factors to help clinicians identify high-risk patients for early and targeted treatment to prevent hospital-acquired pneumonia.

Methods
This study was conducted under the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. [15]

Search strategy
Systematically Searched 4 English databases (PubMed, EMBASE, The Cochrane Library, and Web of Science) and 4 Chinese databases (CNKI, CQVIP, Sinomed, and WAN FANG) from inception until October 20, 2022.All studies involving risk factors of HAP in patients with hip fractures will be considered using a search strategy that combines keywords and free words.To avoid omitting the literature, we have reduced the restrictions on medical subject words and added more free words.The main medical subject words were as follows: "Hip," "Hip Fractures," "Femoral Neck Fractures," and "Pneumonia."Simultaneously, the references of included studies and relevant reviews were manually reviewed.

Eligibility criteria
Inclusion criteria were as follows: Study types: Cohort study or case-control studies; Participants: All the patients with hip fractures who have been hospitalized; Outcomes: Original studies that explore the relationship between demographic factors, comorbidity factors, surgical factors, and laboratory factors with Hospital-Acquired Pneumonia; and Data: Full text can be obtained, and sufficient data were published for estimating an odds ratio (OR) with 95 % confidence interval (95 % CI) by multivariate logistic regression.
Exclusion criteria were as follows: Study types: Those studies that are reviews, letters, comments, case reports, abstracts, and animal trials; Participants: Patients with hip fractures were hospitalized for less than 48 hours or caused by polytrauma; Outcomes: No interesting outcomes were reported; and Data: Duplicate data or unable to calculate OR with 95 % confidence interval (95% CI).

Data extraction
After removing duplicate records from the retrieved literature, the titles and abstracts of all articles were independently reviewed by the researchers based on risk factors.Upon meeting the inclusion criteria, the full texts underwent further evaluation.If the full-text screening was also successful, the researchers extracted the following data (factors identified through multivariate logistic regression): first author's name, year of publication, country, study type, number of cases, number of patients with HAP, incidence of HAP, mean age of patients and controls, male-to-female ratio of patients and controls, as well as significant risk factors.Additionally, odds ratios (ORs) and 95% confidence intervals (CIs) were extracted.Two researchers (W.Y. and X.J.S.) independently conducted the entire process, quantifying inter-reviewer agreement using the Kappa coefficient to ensure unbiased evaluation.Any discrepancies were resolved through thorough discussion to reach a consensus.If consensus couldn't be reached, an independent arbitrator (W.B.D.) was consulted for resolution.

Quality assessment
The Newcastle-Ottawa scale (NOS) was used to evaluate the quality of the included study, mainly based on 3 items: the selection of the study population (0-4 stars), the comparability between groups (0-2 stars), and the measurement of exposure outcomes (0-3 stars).The overall score of NOS is between 0 to 9stars, and ≥ 7 stars were considered a high-quality study.Two researchers (W.Y. and X.J.S.) will independently assess the included studies' quality.Finally, 35 articles (including 21 English articles and 14 Chinese articles) with research quality ≥ 7 stars were included in the meta-analysis (inter-reviewer agreement abstracts kappa = 0.82 ± 0.03; full-texts kappa = 0.66 ± 0.05) (Fig. 1).The disagreements between the 2 authors will be resolved by discussion with the third author (Q.M.L.).

Statistical analysis
We excluded risk factors that were only reported in a single publication.Subsequently, 2 authors (W.Y. and X.J.S.) decided to group together identical or nearly identical risk factors.The adjusted OR with a 95% CI from the original studies was extracted by both authors and recorded in a standardized data extraction table.Statistical analyses were conducted to examine the effect estimates of both the adjusted and unadjusted studies, with the aim of determining if any significant differences existed.In cases where only frequency data were provided, the ORs and CIs were independently calculated by the 2 authors.Any articles with missing relevant data were addressed by contacting the corresponding authors; otherwise, they were excluded.Disagreements were settled through discussions and negotiations between the 2 authors.If unresolved, consultations were held with the senior researcher (W.B.D.).
The consistency index (I 2 ) was used to evaluate the statistical heterogeneity between studies.When I 2 < 50% or Q-test P > .1, the fixed effect model was used; When I 2 > 50% or Q-test P < .1, a random effect model was used, indicating heterogeneity between studies.The effect of individual studies that yield meta-analysis estimates by omitting one study at a time to characterize the extent to which removing individual studies affects the estimates (Sensitivity analysis).Subgroup analyses were employed to ascertain the relationship between postoperative HAP after hip fracture and related study characteristics (Advanced age, Hypoalbuminemia and the number of comorbidities) as a possible source of heterogeneity.When 10 or more studies were included, the publication bias was evaluated by funnel plots and Begg's and Egger's tests.P < .05,and asymmetric funnel plots indicated significant publication bias.P value < .05 in the overall effect test suggests that the risk factors were statistically significant.
Review Manager version 5.

Study characteristics and quality assessment
The essential characteristics of the included studies are shown in Table 1.A total of 35 articles have been included since 2015, including 25 case-control studies and 10 cohort studies.The included articles comprised retrospective studies, and subgroup analysis did not reveal any significant heterogeneity.The study population was drawn from 6 countries, with the majority being from Asian countries (China and Korea), while 7 articles originated from Europe and the United States.Notably, the articles from Asia primarily focused on advanced age and COPD, whereas the articles from Europe and the US primarily examined sex and the time from injury to operation.The summary of risk factors of HAP reported in these studies is shown in Table 2.A total of 43 risk factors were reported, with advanced age mentioned in 19 articles, and time from injury to operation, COPD, and hypoalbuminemia mentioned in 14 or more articles.
The methodological quality assessment included in the studies is shown in Table 1, using the NOS scale, with a score range of 0-9 stars.The quality assessment results of 35 studies were as follows: 9 stars in 12, 8 stars in 14, and 7 stars in 9.As a result, the quality of each study is higher.Detailed quality assessment results can be found in Table S1, Supplemental Digital Content.

Meta-analysis results
The point prevalence rate of HAP in 35 studies was between 1.1% and 25.2%, the overall cumulative prevalence rate was 8.9% (95% CI: 0.071-0.108;I 2 = 99%), and heterogeneity could not be solved by sensitivity analysis (Fig. 2).For the same risk factor, because the definition of each original study was different, some studies defined it as a continuous variable, while others defined it as a dichotomous variable.Therefore, we labeled the variable types of risk factors and combined the statistics respectively.When necessary, we also carried out a subgroup analysis for the same risk factors at different stratification levels (such as Advanced age and Hypoalbuminemia).Secondly, we divided the risk factors into 4 categories.In each category, there was a risk factor reported more than 10 times by previous studies: Demographics -Advanced age, Comorbidity -COPD, Surgical -Time from injury to operation, and Laboratory -Hypoalbuminemia.The detailed results of each factor are shown in Table 3.
The remaining 2 studies [6,18] reported the relationship between advanced age (stratification variable) and HAP, and there was Detailed data on potential risk factors for hospital-acquired pneumonia.

Included in publication bias
Advanced age 19 minor heterogeneity among the studies (Fig. 3C-E; Table 3).
A funnel plot for COPD was used to evaluate publication bias (Fig. 5B).Meanwhile, we performed Begg's and Egger's tests (in Figure S2B, Supplemental Digital Content, http://links.lww.com/MD/L747) for COPD.The results showed P > .05,indicating no publication bias for COPD.
The remaining 9 studies [16,21,22,24,26,27,29,37,38] reported the relationship between time from injury to operation (dichotomous variable: ≥48 hours vs <48 hours) and HAP.The results showed minor heterogeneity between the studies (P = .31,I 2 = 15%; Fig. 4C; Table 3).Summarizing the results of these studies demonstrated that the incidence of HAP in patients with hip fractures who took more than 48 hours from injury to operation was 3.59 times higher than that in patients less than 48 hours (Fixed-effects model; OR 3.59, 95% CI 2.88-4.48;Fig. 4C; Table 3).
A Funnel plot for hypoalbuminemia (dichotomous variable) was used to evaluate publication bias (Fig. 5C).We also performed Begg's and Egger's tests (in Figure S4B and C, Supplemental Digital Content, http://links.lww.com/MD/L749).The results showed P > .05,indicating no publication bias among each subgroup.

Discussion
HAP is a common complication in patients with hip fractures, with an incidence of 8.9% in our study, similar to the previously reported range of 4.0% to 9.0%. [9,39,42]In addition to the widely reported risk factors such as advanced age, COPD, time from injury to operation, and hypoalbuminemia, we also found that 17 other factors had statistical significance with HAP, including fifteen risk factors (Males, functional status-dependent, history of smoking, history of stroke, CVA, history of cancer, cognitive function dysfunction, number of comorbidities, ASA ≥ 3, duration of surgery ≥ 2h, ICU, extramedullary operation, anemia, high RDW, and high Cr) and 2 protective factors (High BMI and intrathecal anesthesia).Therefore, a complete understanding and discussion of these risk factors were beneficial to reduce mortality and improving prognosis. [6,11,17,43]revious studies [2,11,23,25] have suggested that advanced age (continuous variable) was an independent predictor of HAP, which was consistent with our research.However, the advanced age (dichotomous variable) definition varies among studies.To further assess the age cutoff for a significantly increased risk of HAP, we analyzed the age subgroups.Compared with other age groups, the probability of pneumonia occurring over 90 years old was increased considerably.][46] In the actual situation, advanced age as a single indicator to predict pneumonia is too single, and we should combine age with other factors for comprehensive analysis. [18,22,29,30]Another critical factor was gender.Ekström et al found that males were more than twice as likely as females to suffer from HAP. [14] Most studies believe this is caused by more disease exposure and a wider history of smoking in males than females. [4,6,9,40]Therefore, smoking history was also a significant risk factor for HAP.In terms of patient BMI, we found that high BMI was a protective factor for HAP, which was interesting because high BMI in the past was associated with poor prognosis of patients. [47,48]In this regard, Jiang and Byun et al explained that the lower the BMI of patients, the higher the possibility of swallowing suffering, and the rate of aspiration will increase. [16]OPD is a significant risk factor for the occurrence and development of HAP.Lareau et al found that due to the longterm impact of COPD, the structure and function of patients' lungs and thorax changed, resulting in decreased compliance, imbalance of ventilation and blood flow, and irreversible lung injury. [49]][33] Poole et al believed that patients with hip fractures combined with stroke had decreased living ability to varying degrees and were prone to dysphagia and HAP, which required early intervention for protection. [50]In a nationwide cohort study, Søgaard et al confirmed the correlation between cancer and HAP. [51][54] In our study, we emphasized the subgroup analysis of the number of comorbidities.The results showed that the higher the number of comorbidities, the higher the incidence of HAP.When the Number of comorbidities ≥ 3, the incidence of HAP can be increased by 6.6 times.Combining age with the number of comorbidities as a concern value can improve the accuracy of the prediction of HAP. [14,29,38]n this study, the time from injury to surgery in the HAP group was significantly longer than in the non-HAP group.][37] Klestil et al mentioned in a recent review that patients with complications can usually benefit from surgery within 24 hours. [55]herefore, patients with hip fractures must be hospitalized as soon as possible to evaluate whether to carry out surgical treatment.If patients need surgical treatment, then the preoperative ASA score, [11,56] the type of anesthesia, [26,30] the type of operation, [11,25] duration of surgery, [22,27] and whether or Medicine not to enter ICU monitoring after surgery [20,57] may increase the incidence of HAP.The specific mechanism varies from individual to individual.We also found that the mechanical ventilation time was related to HAP. [20,34] However, there are few related studies, so the robustness of the results remains to be confirmed.In terms of laboratory factors, hypoalbuminemia is often considered an important indicator of malnutrition and a common risk factor for surgical and inpatients. [58,59]On one side, fracture healing and muscle recovery require much protein.When the protein is insufficient, it will lead to weakened limb function, affect fracture healing, and increase bed rest time; others, the deficiency of serum albumin causes the decrease of plasma colloid osmotic pressure and the increase of interstitial fluid, which may lead to pleural effusion, thus increasing the incidence of HAP. [29,60]In contrast, high RDW and Cr levels are associated with HAP.When the RDW level is high, the number of mature red blood cells in the body decreases, which damages the blood microcirculation and reduces the tissues' oxygen supply. [61,62]The higher Cr level suggests the patient may have nephritis, leading to secondary pneumonia. [63,64]Anemia may also cause the occurrence of HAP.Diet, chronic diseases, tumors, consumption after fracture, and blood leakage at the fracture site may all cause anemia in patients and increase the risk of HAP. [6,32]dditionally, we found studies evaluating the relationship between hyperglycemia and HAP.Although there was no statistical significance between the two in this study, we believe this is because fewer studies were included. [17,30]Rueda et al have demonstrated that poor blood glucose control increases the risk of pneumonia. [65]We are looking forward to more high-quality studies in the future to confirm the relationship between hyperglycemia and HAP.
This study has the following notable strengths: First, this is the first meta-analysis on risk factors of HAP in patients with hip fractures.Second, compared with the previous meta-analysis of risk factors, we have retrieved more databases and included more articles.Third, the inclusion of a substantial amount of Asian literature for the first time has addressed the potential influence of racial genetics, reducing the risks associated with regional bias and facilitating the generalization of research findings.
Nevertheless, this study has several limitations: Firstly, Significant heterogeneity was found in selected studies.Secondly, Only the factors after multivariate logistic regression are included.Although this improves the study's accuracy, it will cause some factors related to HAP not to be included.Thirdly, RCT studies were not included to focus on this topic, and we need more RCT studies to confirm our results.Lastly, due to the inaccuracy of medical translation, we did not include highquality research in other languages.

Conclusions
In conclusion, this meta-analysis of 35 articles and 337818 patients comprehensively assessed the prevalence and risk factors for HAP in patients with hip fractures.The study found that HAP had an incidence of 8.9% and identified 21 significant risk factors, including advanced age, COPD, hypoalbuminemia, male gender, functional status-dependent, history of smoking, history of stroke, CVA, history of cancer, cognitive function dysfunction, number of comorbidities, ASA ≥ 3, duration of surgery ≥ 2 hours, ICU, extramedullary operation, anemia, high RDW, and high Cr.These findings can help clinicians identify patients at risk of HAP and implement preventive measures to reduce the incidence of this devastating complication during hospitalization.Further studies are needed to confirm these risk factors and develop effective prevention strategies.

3 (
The Cochrane Collaboration, Oxford, UK), STATA 15.0 (STATA Corporation, College Station, TX), and R software version 4.0.3(R 4.0.3 for Windows; GitHub, San Francisco, CA) were used for all statistical analyses.

Figure 1 .
Figure 1.Flow diagram of studies screening.

9 ASA=
American Society of Anesthesiologists status scale, BMI = Body mass index, BNP = B-natriuretic peptide, CKMB = Creatine kinase MB blood, COPD = Chronic obstructive pulmonary disease, Cr = Creatinine, CVA = Cardiovascular Accident, ICU = Intensive care unit, NA = not available, NISS = National institute of health stroke scale, RDW = Red blood cell volume distribution width, RV GLS = Right ventricular global longitudinal strain.
American Society of Anesthesiologists status scale, BMI = body mass index, BNP = B-natriuretic peptide, CKMB = creatine kinase MB blood, COPD = chronic obstructive pulmonary disease, Cr = creatinine, CVA = cardiovascular accident, ICU = intensive care unit, NISS = National institute of health stroke scale, RDW = red blood cell volume distribution width, RV GLS = right ventricular global longitudinal strain.www.md-journal.com

Figure 3 .
Figure 3. Forest plots for advanced age. A. Sensitivity analysis for advanced age as a continuous variable (per year increase); B. Subgroup analysis for advanced age as a dichotomous variable (age > 70 vs ≤70 and age > 80 vs ≤80); C. Forest plot for advanced age as a stratification variable (60-69 years vs 70-79 years); D. Forest plot for advanced age as a stratification variable (60-69 years vs 80-89 years); E. Forest plot for advanced age as a stratification variable (60-69 years vs ≥90 years).

Figure 4 .
Figure 4. Forest plots for the other most frequently mentioned risk factors (> 10 articles).A. Sensitivity analysis for COPD as a dichotomous variable; B.Sensitivity analysis for time from injury to operation as a continuous variable (per hour increase); C. Forest plot for time from injury to operation as a dichotomous variable (≥48 vs <48 hours); D. Sensitivity analysis after subgroup analysis of hypoalbuminemia as a dichotomous variable (hypoalbuminemia < 3.0 vs ≥3.0g/L and hypoalbuminemia < 3.5 vs ≥3.5 g/L).COPD = chronic obstructive pulmonary disease.

Figure 5 .
Figure 5. Funnel plots for the risk factors included 10 or more studies.A. Funnel plot for advanced age subgroup; B. Funnel plot after sensitivity analysis for COPD; C. Funnel plot after sensitivity analysis for hypoalbuminemia subgroup.COPD = chronic obstructive pulmonary disease.

Table 3
The Results of the meta-analysis of potential risk factors.